Hydroxamic acids play a number of roles in a range of biological and biochemical processes and systems. Accordingly, hydroxamic acids have been and continue to be investigated and their chemistry and biochemistry are well documented. Hydroxamic acids have been reported to act in a number of different capacities, including as antibacterial, antifungal and anticancer agents, and as specific enzyme inhibitors. Use of hydroxamic acids as metal ion chelators has been reported. A number of groups have reported on the investigation of hydroxamic acids in human clinical trials as drugs for the treatment of several diseases.
Pathways for synthesizing hydroxamic acids are of interest due to their pharmacological, toxicological and pathological properties. Approaches for synthesizing hydroxamic acids have been reported, including reactions involving the acylation of hydroxylamines. Other pathways for synthesizing hydroxamic acids have been reported, including reactions involving the oxidation of arylacylamides.
Preparation of Hydroxamic Acids Involving the reaction of nitroso compounds has been reported. Nitroso compounds have been reported as exhibiting a high reactivity of the nitroso group. The polarization of the nitrogen-oxygen bond, resembling that of the carbon-oxygen bond in a carbonyl group, results in susceptibility of the nitroso group to the addition of nucleophiles. Preparation of N-arylhydroxamic acids involving the reaction of aromatic nitroso compounds with oxoacids in the presence of acidic media has been reported. The conversion of aromatic nitroso compounds into hydroxamic acids using thiamine-dependent enzymes, such as α-ketoglutarate dehydrogenase, pyruvate decarboxylase and transketolase, has been reported (see, for example, Corbett, M. D.; Corbett, B. R.; Doerge, D. R. J. Chem. Soc. Perkin Trans. 11982, 345 and references therein; and Corbett, M. D.; Doerge, D. R.; Corbett, B. R. J. Chem. Soc. Perkin Trans. 11983, 765).
Many groups have reported that organocatalytic reactions provide an efficient means for metal-free carbon-nitrogen (C—N) bond and carbon-carbon (C—C) bond formation.
Examples of organocatalytic C—N bond formation reactions, including N-nitroso aldol reaction of enamines selectively forming N-hydroxyaminoketones, have been reported (see, for example, Yamamoto, H. and Momiyama N. J. Am. Chem. Soc. 2005, 127; 1080; and Momiyama, N.; Yamamoto, Y.; Yamamoto, H. J. Am. Chem. Soc. 2007, 129, 1190).
Many groups have repotted that N-heterocyclic carbene catalysts can be used for metal-free C—C bond formation via the nucleophilic “Breslow intermediate”, or the homoenolate equivalent species. Depending on the electrophile, different types of reactions are possible via both intermediates.
Examples of the former path have been reported, including benzoin condensation, wherein an aryl aldehyde acts as the electrophile, and the Stetter reaction, wherein a Michael accepter acts as the electrophile. Other examples of this path have been reported, including redox reactions of α-functionalized aldehydes to form the corresponding esters or amides.
Examples of C—C bond forming reactions involving the homoenolate equivalent species have been reported, including lactonization, cyclopentannulation, and azannulation.
Approaches for the preparation of hydroxamic acids using readily available reactants and catalysts are desired.